The overriding goal of this proposal is to define the mechanisms of the exaggerated adverse cardiovascular effects of cocaine in the setting of moderate dilated cardiomyopathy. Cocaine use remains a serious public health concern. Among the numerous cardiovascular complications of cocaine use, cardiomyopathy remains perhaps the most enigmatic. It is unclear whether the frequently reported association between cocaine use and cardiomyopathy is causal or if it represents an enhanced interaction between cocaine and a pre-existing, even mild, cardiomyopathy. In the prior period of support we have demonstrated that cocaine indeed has enhanced chronotropic, inotropic and coronary vasoconstrictor effects in cardiomyopathy, and this combination results in impaired global cardiac function. The current proposal aims to define the mechanisms behind these observations. Again using primarily the pacing-induced model of cardiomyopathy in conscious dogs, we will determine if the exaggerated chronotropic and inotropic effects of cocaine in cardiomyopathy are due to abnormalities in baroreflex function and resultant enhanced central sympathetic efferent activity. We will also determine if these features of cardiomyopathy prevent the normal development of cardiovascular tolerance to repeated doses of cocaine. Lastly we will examine the role of altered adrenergic, cholinergic and endothelial function in mediating the enhanced coronary vascular effects of cocaine in this substrate. These studies will be performed in a state-of-the-art facility at Allegheny University of the Health Sciences/Allegheny Campus featuring 2 operating rooms, a catheterization laboratory and 6 recording rooms for the conduct of experiments. The laboratory is integrated into the Cardiovascular and Pulmonary Research Institute, under the direction of Dr. Stephen Vatner. This close working relationship not only allows for ample technical support but also provides a rich academic environment featuring numerous conferences, collaborations and a free exchange of ideas. The proposed project will allow for the principal investigator's ongoing development as a large animal cardiovascular physiologist. New skills to be mastered include assisting in the surgical creation, management and use of novel models including chronically indwelling coronary and carotid catheters and performance of isolated myocyte and cellular calcium handling studies. These new techniques will contribute to the ongoing maturation of the principal investigator into a clinician- scientist capable of the independent design and conduct of relevant cardiovascular studies.